U.S. patent number 5,516,527 [Application Number 07/960,186] was granted by the patent office on 1996-05-14 for dispensing device powered by hydrogel.
This patent grant is currently assigned to Pfizer Inc.. Invention is credited to William J. Curatolo.
United States Patent |
5,516,527 |
Curatolo |
May 14, 1996 |
Dispensing device powered by hydrogel
Abstract
This invention relates to devices useful for the controlled
delivery of one or more beneficial agents to an environment of use.
More specifically, this invention concerns such devices which are
powered by hydrogel. This invention also relates to the controlled
delivery of one or more beneficial agents to an aqueous environment
of use through the use of such hydrogel powered dispensing devices.
Also disclosed are methods for the controlled delivery of one or
more beneficial agents to an aqueous environment of use which
comprises administering to or otherwise placing the devices of this
invention in the environment of use.
Inventors: |
Curatolo; William J. (Niantic,
CT) |
Assignee: |
Pfizer Inc. (New York,
NY)
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Family
ID: |
23142114 |
Appl.
No.: |
07/960,186 |
Filed: |
October 9, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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655228 |
Feb 12, 1991 |
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296464 |
Jan 12, 1989 |
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Current U.S.
Class: |
424/461; 424/451;
424/473; 424/462; 424/464; 424/482; 424/480 |
Current CPC
Class: |
A61M
31/002 (20130101); A61K 9/0004 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 31/00 (20060101); A61K
009/62 (); A61K 009/26 () |
Field of
Search: |
;424/451,461,462,464,413,480,482 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1238273 |
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Jun 1988 |
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CA |
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1242394 |
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0052917 |
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EP |
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169105 |
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Jan 1986 |
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EP |
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190969 |
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EP |
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233009 |
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Aug 1987 |
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EP |
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248447 |
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250374 |
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EP |
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253541 |
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Jan 1988 |
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EP |
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378404 |
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Jul 1990 |
|
EP |
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3629994 |
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Mar 1986 |
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DE |
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2140687 |
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Dec 1984 |
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GB |
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2150830 |
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Jul 1985 |
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GB |
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2155787 |
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Oct 1985 |
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GB |
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2174299 |
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Nov 1986 |
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GB |
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2189995 |
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Apr 1987 |
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GB |
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2193632 |
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Feb 1988 |
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GB |
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Other References
S Janicki, et al., "Gastrointestinal Therapeutic System Delivering
of a Water Insoluble Drug: Isosorbide Dinitrate (ISDN)", Pharmazie
42:95-96 (1987)..
|
Primary Examiner: Venkat; Jyothsan
Attorney, Agent or Firm: Richardson; Peter C. Benson; Gregg
C. Olson; A. Dean
Parent Case Text
This is a continuation of application Ser. No. 07/655,228, filed on
Feb. 12, 1991, now abandoned, which is a continuation of
application Ser. No. 07/296,464 filed on Jan. 12, 1989, now
abandoned.
Claims
What is claimed is:
1. A dispensing device for releasing a drug to an external
environment which comprises: a capsule containing a plurality of
dispensing devices, each dispensing device comprising
(a) an innermost hydrogel layer, said innermost hydrogel layer not
including drug;
(b) a second layer, said second layer surrounding said innermost
layer and said second layer comprising a mixture comprising one or
more drugs and from about 50 to about 95 weight percent hydrogel,
said hydrogel in said second layer being different from said
hydrogel in said first layer; and
(c) a porous coating which surrounds the mixture, said mixture in
communication through said pores with the external environment, and
said pores having a pore size sufficient to allow passage of the
drugs through to the external environment
wherein the rate of drug release is relatively independent of the
solubility of the drug.
2. The dispensing device according to claim 1 wherein the
beneficial agent is a water insoluble drug.
3. The dispensing device according to claim 2 wherein the hydrogel
is polyethylene oxide.
4. The dispensing device according to claim 3 wherein the coating
comprises cellulose acetate.
5. The dispensing device according to claim 1 wherein the mixture
additionally comprises an osmotically effective solute.
6. The dispensing device according to claim 2 wherein the pores
have a diameter greater than the particle size of the water
insoluble drug.
7. The dispensing device according to claim 4 wherein the coating
additionally contains at least one hole.
8. A method for the controlled delivery of one or more beneficial
agents to an environment of use which comprises placing the device
of claim 1 into the environment of use.
9. The device as recited in claim 1 wherein the mixture comprises
at least two drugs and the rate of drug release is relatively
independent of the solubility of the drugs.
10. The device as recited in claim 1 wherein said device excludes a
semi-permeable coating.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to devices useful for the controlled
delivery of one or more beneficial agents to an environment of use.
More specifically, this invention concerns such devices which are
powered by hydrogel. This invention also relates to the controlled
delivery of one or more beneficial agents to an aqueous environment
of use through the use of such hydrogel powered dispensing devices.
Further, still, this invention is concerned with devices for the
controlled delivery of one or more beneficial agents to the
physiological fluid of animals including mammals such as human
beings.
2. General Background of the Invention
The desirability of controlled release of beneficial agents into an
environment of use such as the physiological fluid of animals
including mammals such as human beings is well known to those
skilled in the relevant art. Controlled delivery of beneficial
agents such as drugs can, for example, result in a relatively
constant concentration of such agents in the physiological fluids
of an animal instead of the more dramatic rises and subsequent
decreases in concentration of such agents usually associated with
periodic dosing. Furthermore, controlled delivery of drugs can
eliminate certain deleterious effects sometimes associated with a
sudden, substantial rise in the concentration of certain drugs.
A variety of devices for the controlled delivery of beneficial
agents have been described. Certain of those devices employ the
physical phenomenon of diffusion for their operation. Examples of
such diffusion driven devices are disclosed in U.S. Pat. No.
4,217,898. Other devices have been described which operate with the
principle of colloidal osmotic pressure. Examples of such
osmotically driven devices are disclosed in U.S. Pat. Nos.
3,845,770; 3,995,631; 4,111,202; 4,160,020; 4,439,196 and
4,615,698. Devices which employ a swellable hydrophilic polymer
which polymer exerts pressure on a container and thereby forces
drug therefrom is disclosed in U.S. Pat. No. 4,180,073. U.S. Pat.
No. 4,327,725 discloses a device which employs a layer of fluid
swellable hydrogel to force beneficial agent out of the device
through a specified and defined passageway. Other hydrogel powered
devices containing such a passageway for delivery of beneficial
agents are disclosed in GB 2,140,687A.
Applicant's copending application, assigned to the assignee hereof
and filed concurrently herewith entitled "Dispensing Devices
Powered by Lyotropic Liquid Crystals" bearing applicant's docket
number PC7540/GCB, discloses dispensing devices, powered by
lyotropic liquid crystals, for the controlled delivery of one or
more beneficial agents to an environment of use.
It is an object of this invention to provide devices for the
controlled delivery of one or more beneficial agents to an
environment of use. Another object of this invention is to provide
devices powered by hydrogel which will effect the controlled
delivery of one or more beneficial agents to an aqueous environment
of use. Yet another object of this invention is to provide devices
powered by hydrogel for the controlled delivery of one or more
beneficial agents to the physiological fluids of an animal
including a human being. This invention also has as an object the
provision of a device to controllably deliver one or more
beneficial agents which are insoluble or substantially insoluble in
water or physiological fluids. Another object still of this
invention is to provide devices powered by hydrogel which do not
require a specified and defined passageway to operate but, instead,
comprise a plurality of pores. It is another object of this
invention to provide devices powered by hydrogel which do not
require a semi-permeable coating, but, instead, can employ a
coating which is permeable to the beneficial agent. Further still,
it is an object of this invention to provide devices powered by
hydrogel which can assume a variety of shapes and sizes and devices
which can be delivered to an environment of use in a capsule.
It is also an object of this invention to provide methods for the
controlled delivery of one or more beneficial agents to an
environment of use by administering to or otherwise placing the
device of this invention into the environment.
These and other objects of this invention will be readily apparent
to those skilled in the relevant art enabled by the disclosure
herein.
SUMMARY OF THE INVENTION
This invention concerns devices for the controlled delivery of one
or more beneficial agents to an environment of use which devices
comprise a mixture of one or more beneficial agents and hydrogel
surrounded by a coating of a material that is permeable to water
and/or aqueous medium such as physiological fluid and which coating
contains one or more holes and/or a plurality of pores. The pores
in the coating can be formed by mechanical/physical means or result
from dissolution of a porosigen in the coating upon placing the
devices in an aqueous environment of use.
This invention also concerns devices for the controlled delivery of
one or more beneficial agents to an aqueous environment of use
which devices comprise two adjacent layers, the first layer
comprising a mixture of one or more beneficial agents and hydrogel
and the second layer comprising hydrogel of the same or different
composition as the hydrogel in the first layer. Such devices have a
coating comprising a material which is permeable to water and/or
aqueous medium and which contains one or more holes and/or a
plurality of pores such as the devices described above.
All of the devices of this invention optionally can include therein
one or more excipients and/or osmotically effective solutes.
This invention also relates to capsules which contain one or more
of the devices as described above.
Further, this invention concerns methods for the controlled
delivery of one or more beneficial agents to an aqueous environment
of use which comprise administering to or otherwise placing the
devices and/or the capsules of this invention in the environment of
use.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of one embodiment of the device (1) of
this invention in the shape of a tablet.
FIG. 2 is a cross-sectional view taken along line 2--2 of the
device (1) shown in FIG. 1.
FIG. 3 is a cross-sectional view of another embodiment of the
device (1) which is taken along line 2--2 of the device (1) shown
in FIG. 1 which device comprises two layers (6 and 7) within the
surrounding coating (3) of the device (1).
FIG. 4 is a cross-sectional view through the axis of another
embodiment of the device (1) of this invention wherein the device
(1) is a sphere or is substantially spherical in shape.
FIG. 5 is a cross-sectional view through the axis of another
embodiment of the device (1) of this invention wherein the device
(1) is a sphere or is substantially spherical in shape and which
comprises two-layers (6 and 7) within the surrounding coating (3)
of the device (1).
FIG. 6 is a cross-sectional view of another embodiment of the
device (1) which is taken along line 2--2 of the device (1) shown
in FIG. 1 which comprises two layers (6 and 7) within the
surrounding coating (3) of the device (1).
DETAILED DESCRIPTION OF THE DRAWINGS
FIGS. 1-6 depict certain embodiments of the devices of this
invention and are meant to be illustrative of such embodiments of
the invention herein. The Figures are not to be construed as
limiting in any way the scope of this invention to the embodiments
depicted therein. Further, the various components of the devices
depicted in the Figures are representational and are not
necessarily drawn to scale.
FIG. 1 shows one embodiment of the device (1) of this invention in
the form of a tablet containing a plurality of pores (2).
FIG. 2 is a cross-sectional view taken along line 2--2 of FIG. 1
and shows the coating (3) of the device (1) which contains a
plurality of pores (2) in and through the coating (3). A mixture
(6) of one or more beneficial agents represented by dots (4) and
hydrogel represented by wavy lines (5) is contained within the
surrounding coating (3).
FIG. 3 is a cross-sectional view of another embodiment of the
device (1) shown in FIG. 1 wherein the device (1) comprises two
layers (6 and 7) within the surrounding coating (3). FIG. 3 is a
cross-sectional view taken along line 2--2 of FIG. 1 and shows the
coating (3) of the device (1) which contains a plurality of pores
(2) in and through the coating (3). Contained within the
surrounding coating (3) are a first layer (6) which comprises a
mixture of one or more beneficial agents represented by dots (4)
and hydrogel represented by wavy lines (5) and a second layer (7)
which comprises hydrogel represented by wavy lines (8) which can be
the same or different than hydrogel (5). Layer (7) is adjacent to
layer (6) and comprises an area in contact therewith.
FIG. 4 is a cross-sectional view through the axis of another
embodiment of the device (1) of this invention wherein the device
is a sphere or is substantially spherical in shape. The device (1)
contains a plurality of pores (2) in and through the coating (3).
Within the surrounding coating (3) is a mixture (6) of one or more
beneficial agents represented by dots (4) and hydrogel represented
by wavy lines (5).
FIG. 5 is a cross-sectional view through the axis of another
embodiment of the device (1) of this invention wherein the device
(1) is a sphere or is substantially spherical in shape. The device
(1) contains a plurality of pores (2) in and through the coating
(3). Within the surrounding coating (3) are two layers (6 and 7).
The outermost layer (6) comprises a mixture of one or more
beneficial agents represented by dots (4) and hydrogel represented
by wavy lines (5) and the innermost layer (7) comprises hydrogel
represented by wavy lines (8) which can be the same or different
than hydrogel (5).
FIG. 6 is a cross-sectional view of another embodiment of the
device (1) shown in FIG. 1 which view is taken along line 2--2 of
FIG. 1 and which device (1) comprises two layers (6 and 7) within
the surrounding coating (3). The coating (3) contains a plurality
of pores (2) in and through the coating (3). Contained within the
surrounding coating (3) are an outermost layer (6) which comprises
a mixture of one or more beneficial agents represented by dots (4)
and hydrogel represented by wavy lines (5) and an innermost layer
(7) which comprises hydrogel represented by wavy lines (8) which
can be the same or different than hydrogel (5).
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to devices powered by hydrogel for the
controlled delivery of one or more beneficial agents to an
environment of use.
The hydrogels employed in the various embodiments of the devices of
this invention are well known to those skilled in the relevant art.
For example, U.S. Pat. No. 4,327,725 describes various hydrogels
and the teachings thereof concerning such hydrogels are hereby
incorporated herein by reference. The term hydrogel, as used
herein, shall be construed to mean a water swellable polymer or a
combination of two or more such polymers. Such hydrogels, for the
purpose of this invention, comprise polymeric materials which, when
in contact with water or other aqueous medium, will absorb such
water/medium and swell to a certain extent. Such absorption can be
reversible or irreversible and still be within the scope of this
invention. A preferred hydrogel for use in the devices of this
invention is polyethylene oxide (PEO). PEO is commercially
available and can be obtained having a variety of different
molecular weights. For example, PEO can be obtained with molecular
weights of 8K, 14K, 100K, 400K, 600K, 1,000K or 5,000K. The
particular molecular weight of PEO or other hydrogels employed in
the devices of this invention will vary as a function of the pore
size in the coating and the release rate which is to be achieved
for the particular beneficial agent or agents to be delivered.
In the two layer embodiments of the devices of this invention, such
as those shown in FIGS. 3, 5 and 6, the hydrogel of each layer may
be the same or may be different. In the embodiment depicted in FIG.
3, it is preferred that the hydrogel (8) of layer (7) be of a
higher molecular weight than hydrogel (5) of layer (6). Still more
preferably, the hydrogel (8) of such an embodiment as shown in FIG.
3 should be of a sufficiently high molecular weight that
substantially no hydrogel is capable of leaving the device (1)
through the pores (2). However, since certain hydrogels such as PEO
increase in viscosity as a function of increase in molecular
weight, the hydrogel (5) and (8) must be chosen or blended such
that it provides sufficient swelling properties but does not cause
the device to burst. Selection of the appropriate hydrogel (5) and
(8) for such devices is within the skill of those who practice in
the relevant art enabled by the disclosure herein.
The hydrogel employed in the various embodiments of the devices of
this invention can be a blend of, for example, two or more
polymers. By way of example and not of limitation, different
hydrogels comprising blends of PEO polymers of different molecular
weights can be prepared and employed in the devices of this
invention and are deemed within the scope hereof. Such blends can,
for particular beneficial agents, be adjusted to assist in
achieving the desired delivery rates for the agents.
In addition to the hydrogel(s), the devices of this invention may
also contain an osmotically effective solute for the purpose of
providing a colloidal osmotic pressure which is additive with the
swelling pressure of the hydrogel(s). Examples of osmotically
effective solutes are inorganic and organic salts, and sugars. A
preferred composition comprising such a solute contains a range of
0-30% osmotically effective solute. Of course, for the devices of
this invention which are to be employed to deliver a drug to an
animal, any such solute must be pharmaceutically acceptable.
The devices of this invention comprise, in addition to the hydrogel
and the optional osmotically effective solute described above, one
or more beneficial agents. The term beneficial agents as used in
this specification and the accompanying claims includes, by way of
example and not of limitation, any physiologically or
pharmacologically active substance that produces a localized or
systemic effect in animals. The term animals is meant to include
mammals including human beings as well as other animals. The
physiologically or pharmacologically active substance of this
invention need not be soluble in water. Indeed, an advantage of the
devices of this invention is that such insoluble or partially
insoluble substances as well as soluble substances can be delivered
to the environment of use in a controlled fashion by the devices
hereof.
Examples of active substances employed in the devices of this
invention include, without limitation, inorganic and organic
compounds such as drugs that act on the peripheral nerves,
adrenergic receptors, cholinergic receptors, nervous system,
skeletal muscles, cardiovascular smooth muscles, blood circulatory
system, synaptic sites, neuroeffector junctional sites, endocrine
and hormone systems, immunological system, reproductive system,
autocoid systems, alimentary and excretary systems, inhibitors of
autocoids and histamine systems. The drug that can be delivered for
acting on these systems includes anti-depressants, hypnotics,
sedatives, psychic energizers, tranquilizers, anti-convulsants,
muscle relaxants, antisecretories, anti-parkinson agents,
analgesics, anti-inflammatory agents, local anesthetics, muscle
contractants, antibiotics, anti-microbials, anthelmintics,
anti-malarials, hormonal agents, contraceptives, histamines,
antihistamines, adrenergic agents, diuretics, antiscabiosis,
anti-pediculars, anti-parasitics, anti-neoplastic agents,
hypoglycemics, electrolytes, vitamins, diagnostic agents and
cardiovascular drugs. Also included in such active substances are
prodrugs of the above-described drugs. Such drugs or prodrugs can
be in a variety of forms such as the pharmaceutically acceptable
salts thereof. However, a particular advantage of the devices of
this invention is that such beneficial agents, such as the drugs
and prodrugs described above, need not be soluble in water in order
for the devices of this invention to deliver, in a controlled
manner, such agents. It is within the scope of this invention that
the devices can contain more than one beneficial agent.
Devices of this invention are particularly advantageous for
delivering two or more drugs simultaneously. The rate of drug
release is controlled primarily by the extrusion rate of hydrogel
and is relatively independent of the solubility of the incorporated
drugs. Thus two or more incorporated drugs will be released at
absolute rates which depend upon their individual loadings in the
device. For example, devices of the current invention can be used
to co-deliver a sustained dose of an s-blocker, such as prazosin,
and a diuretic, such as polythiazide, for the treatment of
hypertension. For the treatment of cold symptoms, devices of this
invention can be used to deliver a combination of a decongestant,
such as pseudephedrine hydrochloride, and an antihistamine, such as
chlorpheniramine maleate. For treatment of cough/cold symptoms,
three or more drugs can be released in a controlled fashion from a
device of this invention; for example a combination of an
analgesic, a decongestant, an antihistamine, and an antitussive can
be delivered. A person skilled in the art will recognize that the
current invention can be used to provide controlled and sustained
delivery of a wide variety of combinations of drugs.
The beneficial agent of this invention also includes other
substances for which it is desirable and/or advantageous to control
delivery into an environment of use. Examples of such substances
include, but are not limited to, fertilizers, algacides, reaction
catalysts and enzymes.
The devices of this invention also comprise a coating (3) which
surrounds the mixture (6) of one or more beneficial agents (4) and
hydrogel (5) or, in the two layer embodiments hereof, which
surrounds both layers (6 and 7) except for the area in contact
between such layers. The coating (3) comprises at least one water
permeable polymer but, significantly and in contrast to many prior
art devices, the coating need not be semi-permeable. Therefore, the
coating (3) can be freely permeable to low molecular weight
compounds. By way of example and not of limitation, such polymers
for the coating (3) include cellulose acetate, ethyl-cellulose,
silicone rubber, cellulose nitrate, polyvinyl alcohols, cellulose
acetate butyrate, cellulose succinate, cellulose laurate, cellulose
palmitate and the like. For example, suitable coatings are obtained
with cellulose acetate having an average molecular weight of 40K or
60K. Also suitable for the coating (3) of the devices of this
invention are biodegradable polymers which do not degrade
significantly (i.e., break or burst) during the delivery period.
Examples of such biodegradable polymers include polylactic acid,
polyglycolic acid and poly(lactide-coglycolide). A preferred
polymer for the coating (3) is cellulose acetate.
The coating (3) can also comprise one or more porosigens such that,
when the devices of this invention are placed in an environment of
use, said porosigen(s) dissolve and effect the formation of a
plurality of pores (2) in and through the coating (3).
As stated above, the porosigens can be employed alone or in
combination to effect formation of the pores (2) in and through the
coating (3). The ratio of porosigen or porosigens to coating
polymer can be varied as well as the choice of porosigens to be
employed. Such variations are within the skill of those who
practice in the art and will be determined by such factors as the
solubility of the beneficial agent(s), the particle size of the
agent(s), the molecular weight of the hydrogel and the desired rate
of release. Examples of porosigens which will function to form the
pores (2) in and through the coating (3) include inorganic salts
such as sodium chloride, potassium chloride, potassium phosphate
and the like. Other effective porosigens are certain particulate
organic compounds and salts thereof such as glucose, sucrose,
lactose, succinic acid, sodium succinate, sodium carbonate and the
like. Also effective porosigens are water-soluble polymers such as
polyethyleneglycol (PEG), methyl cellulose, hydroxypropylmethyl
cellulose, hydroxypropyl cellulose (HPC), polyethylene oxide (PEO)
and the like. Such pore-forming polymers must, however, have the
ability to form a phase-separated coating when mixed with the
coating forming polymer of this invention. That is to say, the
porosigen polymer and the coating polymer cannot be totally
miscible. Combinations of porosigens such as particulate organic
compounds and salts thereof with inorganic salts and/or
water-soluble polymers can be employed and are within the scope of
this invention. Similarly, inorganic salts with water-soluble
polymers can be employed as porosigens in the devices of this
invention. When the devices of this invention are to be used to
deliver beneficial agents to an animal, the porosigen or porosigens
employed must be pharmaceutically acceptable.
In addition to the formation of pores (2) upon placement of the
devices of this invention into an environment of use through
dissolution of one or more porosigens, the pores (2) can be
preformed. Such preformed pores can be produced by methods well
known to those skilled in the art such as by gas generation in the
coating (3) during formation of the coating (3); etched nuclear
tracking; laser, sonic or mechanical drilling; or electric
discharge. It is preferred, however, that such pores result from
dissolution of porosigen(s) as described above.
In addition to the pores described above, or instead thereof, the
coating can contain one or more holes. The holes may extend through
only the coating on one face of the device or extend through the
entire device. However, it is preferred that for the two layer
embodiments of the devices of this invention of the type
represented in FIG. 3 wherein, in addition to the pores shown or
instead thereof, one or more holes are contained in the coating,
such holes do not extend through the entire device but only extend
through the coating adjacent to the layer comprising beneficial
agent. Such holes are made by standard methods known to those
skilled in the art such as by mechanical, sonic or laser
drilling.
In addition to the above-mentioned components of the devices of
this invention, other common pharmaceutical excipients may be
present. Examples of such excipients include, but are not limited
to, binders such as microcrystalline cellulose, plasticizers such
as polyethyleneglycol-600, and buffers such as sodium
phosphate.
The devices of this invention can be prepared in a variety of sizes
and shapes. The particular size and shape of the device will be
determined, in part, by the particular use to which the device is
to be put. For example, for oral administration of a drug, the
device of this invention can be in the shape of a tablet or caplet,
is of suitable size for containing the desired dosage of drug and
is capable of oral administration. Other shapes of the devices of
this invention include, by way of example and not of limitation,
cylindrical or conical shapes suitable for administration of drugs
intravaginally and/or rectally and convex shaped devices for ocular
administration of drugs.
The devices of this invention can also be administered within a
capsule comprising a water soluble wall. For example, the devices
of this invention can be manufactured to be of suitable size for
inclusion either singly or multiply within a gelatin capsule such
that when the capsule dissolves the device or devices are released
into the environment of use. While the devices to be included
within a capsule can be of a variety of shapes, a preferred
embodiment for such devices is spherical or substantially
spherical. The exact number and size of such devices can and will
be determined according to a variety of factors well known to those
skilled in the art. For example, the environment of use, the
beneficial agent or agents, the amount of beneficial agent and the
rate of release are all factors to be considered in determining the
size, shape and number of devices to be included in such capsules
as well as the composition of the capsule.
While the actual process used to manufacture the devices of this
invention may vary, one such preferred process is described below.
Polymer to serve as the hydrogel (5) is blended according to
standard methods well known to those skilled in the art in a
predetermined ratio (e.g. weight percent) with one or more
beneficial agents (4) and any excipients and/or osmotically
effective solute(s). The ratio used will vary to a greater or
lesser degree depending upon the particular hydrogel, the
particular beneficial agent(s) used and the release rate to be
achieved. Generally, however, the devices of this invention will
comprise hydrogel in an amount from about50 to about 95 weight
percent based on the total weight of the mixture (6) of hydrogel
(5) and beneficial agent(s) (4), and any excipients and/or
osmotically effective solute(s). The hydrogel (5) can comprise more
than one polymer in which case all polymers are blended with the
beneficial agent(s) (4) and any excipients and/or osmotically
effective solute(s) either sequentially or simultaneously.
Optionally and preferably, the polymer(s) is sieved to a desired
mesh cut prior to blending. If the desired device is to comprise
one layer of the blended mixture (6) such as is shown in FIG. 2,
then the resulting blended mixture (6) is pressed into the desired
shape such as a tablet or caplet using a conventional tableting
press such as a Kilian LX-21 rotary tablet press (Kilian and Co.,
Koln, Germany).
Devices (1) of this invention which comprise two layers (6 and 7),
such as those of the type shown in FIG. 3, can be prepared in a
similar but modified manner using a conventional bilayer tablet
press. One layer consists of a mixture of one or more hydrogel
polymers with one or more beneficial agents. The other layer
consists of one or more hydrogel polymers, preferably of higher
viscosity than, and generally of higher molecular weight than, the
hydrogel polymer(s) which are mixed with the beneficial agent(s) in
the first layer.
Spherical or substantially spherical embodiments such as depicted
in FIGS. 4 and 5 can be prepared in a variety of ways known to
those skilled in the art. In a preferred method, such embodiments
are prepared using a Fuji extruder/spheronizer (Fuji Paudal Co.,
Tokyo, Japan) according to methods well known to those skilled in
the art. When concentrically arranged embodiments are desired,
hydrogel core beads are first prepared. These hydrogel beads then
can be coated with a hydrogel/drug mixture using a Freund
CF-granulator (CF-360; Freund Industrial Co., Tokyo, Japan) or a
Glatt GPCG coating apparatus (Glatt Air Techniques, Ramsey,
N.J.).
Following formation of the desired shape in the press or
extruder/spheronizer, coating (3) is applied to the entire surface
of the mixture (6), or the surface of layers (6) and (7) which are
not in contact with each other, or the outer surface of the
outermost layer (6) of the concentric embodiment such as depicted
in FIG. 5. The coating (3), which also can comprise porosigen(s),
is applied to the mixture or outermost layer (6) or layers (6) and
(7) according to standard methods well known to those skilled in
the art. For those devices which are not spherical or substantially
spherical, it is preferred that such coating be applied by spraying
using, for example, a Freund Model HCT-30 Hicoater (Freund
Industrial Co., Tokyo, Japan). For those devices which are
spherical or substantially spherical, it is preferred that such
coating be applied using, for example, a Freund CF-granulator or a
Glatt GPCG coating apparatus as described above. As an example,
when cellulose acetate is employed for the coating, it can be
sprayed as an acetone solution (5%) or as other solutions such as
in acetone/methanol (9:1). Such cellulose acetate coatings from
acetone/methanol solution result in a more opaque coating but have
little or no observable impact on the functioning of the devices of
this invention. The amount of coating (3) to be applied can be
varied to affect the release rate of the devices but will generally
be from about 4 to 50 weight percent of the total device weight
with a range of from about 6 to 50 weight percent for those
coatings (3) comprising porosigen(s).
For devices (1) of this invention which contain coating (3) in
which the plurality of pores (2) is formed by means other than
dissolution of porosigen(s), a preferred amount of coating (3) is
in the range of from about 6 to 25 weight percent with an even more
preferred range being from about 8 to 20 weight percent. If such
coating (3) contains porosigen(s), then a preferred amount of
coating (3) for the devices (1) of this invention is a range of
from about 8 to 30 weight percent with an even more preferred range
being from about 10 to 25 weight percent.
If the coating (3) contains one or more porosigens, then the pores
(2) will be formed in situ when the device (1) is placed in the
environment of use. Of course, while not necessarily advantageous,
the pores (2) of such devices can be preformed by placing the
device first into a suitable aqueous environment then, upon
dissolution or partial dissolution of the porosigen(s), into the
environment of use.
If the coating (3) does not contain any porosigen, then the pores
(2) can be formed by other methods well known to those skilled in
the art. For example, pores (2) in coating (3) can be formed by gas
generation during formation of the coating (3) following
application of the coating mixture to the device. Other processes
to produce pores (2) in coating (3) include the use of etched
nuclear tracking, the use of laser, sonic or mechanical drilling
and the use of electrical discharge. Additionally, in coatings
without porosigens, pores can be formed in the environment of use
by bursting of weak portions of the membrane as a result of the
internal pressure generated by the swelling hydrogel.
A combination of the above described methods for producing pores
(2) in coating (3) can be employed and are within the skill of
those skilled in the art enabled by the disclosure herein. Such
devices are within the scope of this invention.
When employing porosigens to form the pores (2) in coating (3),
particular attention is to be paid to the beneficial agent or
agents to be delivered by the device (1). If the beneficial agent
is soluble, then pore size is not as crucial as when the agent is
insoluble. Indeed, the devices of this invention will function to
controllably release certain agents even though the pore size is
less than 0.1 micron where such agent is soluble. However, where
delivery of an insoluble agent, such as the drug glipizide, is
desired, then the porosigen employed must be such that, upon
dissolution, pores (2) having diameters greater than the particle
size of the agent are formed in and through the coating (3). For
example, sucrose of a selected mesh cut can be employed in a
suspension comprising cellulose acetate to form a coating (3)
which, upon subsequent dissolution of the sucrose will yield pores
(2) of a preselected (i.e., mesh cut) size. Similarly, commercially
available sucrose beads can be so employed. For certain beneficial
agents and/or environments of use, it may be advantageous or
preferable to include more than one porosigen. For example, coating
mixtures which comprise coating polymer, water soluble polymer and
sucrose such as cellulose acetate/polyethylene glycol-600 (1:1)
with 50% particulate sucrose can be suitably employed. The choice
of porosigen or porosigens as well as the amount thereof employed
in the coating mixture can be readily determined by those skilled
in the art enabled by this disclosure.
Similarly, when the pores (2) in coating (3) are formed by means
other than by dissolution of porosigen(s), the nature of the
beneficial agent(s) to be delivered by the device (1) must be
considered to insure that the pores (2) are of a sufficient
diameter as described above. Formation of pores (2) of varying
diameter according to the methods described above are well known to
those skilled in the art.
When the devices of this invention are to contain one or more holes
in the coating (3) or through the device (1), then, after such
devices have been coated as described above, the desired number and
size holes are drilled through the coating or device according to
standard methods such as mechanical, sonic or laser drilling.
Methods for using the devices of this invention include
administration of the appropriate devices to animals via oral
administration or by insertion of the appropriate devices into a
body cavity of the animal. Devices of this invention can also be
used to deliver agents to such environments of use as fish tanks,
soil and aqueous chemical and/or enzymatic reaction systems. In
such cases, the devices are placed into the desired environment of
use. The devices of this invention require that any such
environment of use be either aqueous or provide for contact of the
device with water or other aqueous medium.
The following examples will serve to illustrate the devices of this
invention and are not to be construed as limiting the scope hereof
to those embodiments specifically exemplified.
EXAMPLE 1
Doxazosin mesylate was blended with 20K molecular weight
polyethylene oxide (PEO-20K) in a ratio of 2:98 and the blended
mixture was pressed into 500 mg tablets in a Carver press using
13/32 inch standard concave punches under 2 metric tons for 2
seconds. The tablets were then spray coated with a 9:1
acetone/methanol solution of cellulose acetate (2.2%) and
hydroxypropyl-cellulose (HPC) (2.2%). The weight ratio of cellulose
acetate to HPC in the coating was 1:1, and the final coating was 12
weight percent of the total device weight.
EXAMPLE 2
The procedure of Example 1 was followed up to the coating of the
tablets where the coating mixture was applied to an amount equal to
18.6 weight percent of the total device weight.
EXAMPLE 3
The procedure of Example 1 was followed up to the coating of the
tablets where the coating mixture was applied to an amount equal to
23.8 weight percent of the total device weight.
EXAMPLE 4
Tablets of 500 mg were prepared as follows. Polyethylene oxide (14K
molecular weight) (PEO-14K) was blended with doxazosin mesylate at
a ratio of 9:1 and pressed into 500 mg tablets as described in
Example 1. Then, the tablets were spray coated with a 9:1
acetone/methanol solution of cellulose acetate (2.2%) and HPC
(2.2%). The weight ratio of cellulose acetate to HPC in the coat
was 1:1, and the final coating was 13.1 weight percent of the total
device weight.
EXAMPLE 5
The procedure of Example 4 was followed to form tablets which were
then spray coated with an 8:2 acetone/methanol solution of
cellulose acetate (2.9%) and HPC (4.3%). The weight ratio of
cellulose acetate to HPC in the coating was 2:3, and the final
coating was 14 weight percent of the total device weight.
EXAMPLE 6
The procedure of Example 4 was followed to form tablets which were
then spray coated with an 8:2 acetone/methanol solution of
cellulose acetate (1.5% ) and HPC (3.5%). The weight ratio of
cellulose acetate to HPC in the coating was 3:7, and the final
coating was 13.1 weight percent of the total device weight.
EXAMPLE 7
A blend of PEO of 8K molecular weight (PEO-8K) and doxazosin
mesylate (98:2) was prepared and pressed into 500 mg tablets in a
Carver press using 13/32 inch standard concave punches under 2
metric tons for 2 seconds. The tablets were then spray coated with
a 9:1 acetone/methanol solution of cellulose acetate (3%) and
PEO-8K (3%). The weight ratio of cellulose acetate to PEO-8K in the
coating was 1:1, and the final coating was 12.7 weight percent of
the total device weight.
EXAMPLE 8
A blend of polyethylene oxide (8K molecular weight) (PEO-8K) and
doxazosin mesylate (9:1 ) was prepared and pressed into 500 mg
tablets in a Carver press using 13/32, inch standard concave
punches under 2 metric tons for 2 seconds. The tablets were spray
coated with a 9:1 acetone/methanol solution of cellulose acetate
(3.5%) and polyethylene glycol (molecular weight 600) (PEG-600)
(1.5%). The weight ratio of cellulose acetate to PEG-600 in the
coating was 7:3, and the final coating was 12.5 weight percent of
the total device weight.
EXAMPLE 9
The procedure of Example 8 was followed to produce tablets which
were then spray coated with a 9:1 acetone/methanol solution of
cellulose acetate (3.0%) and PEG-600 (2.0%). The weight ratio of
cellulose acetate to PEG-600 in the coating was 3:2, and the final
coating was 12.9 weight percent of the total device weight.
EXAMPLE 10
The procedure of Example 8 was followed to produce tablets which
were then spray coated with a 9:1 acetone/methanol solution of
cellulose acetate (2.5%) and PEG-600 (2.5%). The weight ratio of
cellulose acetate to PEG-600 in the coating was 1:1, and the final
coating was 13.5 weight percent of the total device weight.
EXAMPLE 11
A blend of 100K molecular weight polyethylene oxide (PEO-100K) and
the insoluble drug glipizide (95:5) was prepared and pressed into
500 mg tablets using a Manesty Type-F3 tablet press (Manesty
Machines Ltd., Liverpool, England). The tablets were spray-coated
with a suspension of sucrose (50/60 mesh) in an acetone solution of
cellulose acetate (2.5%) and PEG-600 (2.5%). The weight ratio of
cellulose acetate to PEG-600 to sucrose in the coating was 1:1:2.
The final coating was 13.7 weight percent of the total device
weight.
EXAMPLE 12
The procedure of Example 11 was followed to produce tablets as
described therein which were then spray coated with suspension of
sucrose (30/40 mesh) in an acetone solution of cellulose acetate
(4%) and PEG-600 (1%). The weight ratio of cellulose acetate to
PEG-600 to sucrose in the coating was 4:1:5. The final coating was
11.8 weight percent of the total device weight.
EXAMPLE 13
The release rates for the devices described in Examples 1-12 were
determined according to the procedures described below.
For those devices which contained doxazosin, the device under study
was placed in an individual well of a USP dissolution apparatus
which well contained 1000 ml of water as the release medium. The
well containing the device was stirred at 100 rpm and aliquots of
the release medium were removed over time. The aliquots were
assayed for doxazosin by measuring UV absorbance at 246 nm.
For those devices which contained glipizide, the device under study
was placed in an individual well of a USP dissolution apparatus
which well contained 1000 ml of USP Simulated Intestinal Fluid
(SIF) without enzymes as the release medium. The well containing
the device was stirred at 100 rpm and aliquots of the release
medium were removed over time. The aliquots were assayed for
glipizide by measuring UV absorbance at 275 nm.
Employing the above described assay procedures, the devices of
Examples 1-12 were assayed for release of the beneficial agent and
the data is shown in the Tables described below.
TABLE I ______________________________________ Percent of Doxazosin
Released over Time from Devices of Examples 1, 2 and 3 Percent
Doxazosin Released Device of Device of Device of Time (hrs.)
Example 1 Example 2 Example 3
______________________________________ 0 0 0 0 1.50 0 0 0 3.17 12.6
1.3 0 4.0 18.4 5.3 0 5.0 25.8 8.9 1.2 5.67 30.7 11.5 2.4 7.67 37.6
18.5 5.0 9.83 52.2 26.9 8.8 11.0 54.6 29.9 10.9 12.25 60.0 35.2
13.2 13.10 61.6 37.6 14.2 22.0 76.5 57.5 29.1 24.0 83.2 61.1 31.8
26.0 85.7 63.6 33.0 ______________________________________
Table I, above, shows the release of doxazosin as percent released
over time of the devices of Examples 1, 2 and 3. The data show that
the rate of release can be varied as a function of the amount of
coating (3) applied to the device. For the devices of Examples 1, 2
and 3, as the amount of coating increased the rate of release
decreased.
TABLE II ______________________________________ Percent of
Doxazosin Released over Time from Devices of Examples 4, 5 and 6
Percent Doxazosin Released Device of Device of Device of Time
(hrs.) Example 4 Example 5 Example 6
______________________________________ 0 0 0 0 1.25 0 -- -- 1.33 --
7.0 23.8 2.0 -- 15.9 35.9 2.16 3.5 -- -- 3.0 -- 30.2 53.0 3.1 9.3
-- -- 4.0 -- 43.8 68.3 4.1 15.4 -- -- 5.0 -- 54.3 80.4 5.16 22.4 --
-- 6.0 -- 61.5 88.1 6.1 28.8 -- -- 7.0 -- 67.8 92.7 7.1 34.5 -- --
7.85 38.7 -- -- 8.0 -- 74.0 96.6 10.33 52.4 -- -- 11.5 57.1 -- --
______________________________________
Table II, above, shows the release of doxazosin as percent released
over time from the devices of Examples 4, 5 and 6. The data show
that the rate of release can be varied as a function of the amount
of porosigen and, hence, pores (2) contained in the coating (3).
For the devices of Examples 4, 5 and 6, the rate of release
increased as the amount of porosigen (i.e., hydroxypropyl
cellulose) in the coating was increased.
Table III, below, presents data showing the release rate of
doxazosin as percent released over time for the device of Example
7.
TABLE III ______________________________________ Percent of
Doxazosin Released over Time from the Device of Example 7 Time
(hrs.) Percent Doxazosin Released
______________________________________ 0 0 0.5 2.7 1.0 13.4 1.5
21.0 2.0 28.9 2.5 36.4 3.0 44.2 3.5 51.5 4.0 57.3 4.5 61.8 5.0 66.1
5.75 70.6 7.17 76.5 23.33 90.8
______________________________________
TABLE IV ______________________________________ Percent of
Doxazosin Released over Time from Devices of Examples 8, 9 and 10
Percent Doxazosin Released Device of Device of Device of Time
(hrs.) Example 8 Example 9 Example 10
______________________________________ 0 0 0 0 0.5 0 0 0 1.0 0 0
10.0 1.5 0 0 22.4 2.0 0 10.9 33.0 2.5 0 20.4 43.4 3.0 1.5 29.1 49.4
3.5 3.9 36.3 54.3 4.0 7.8 41.5 59.5 4.5 11.2 45.4 62.6 5.0 15.2
49.2 65.7 5.75 20.6 52.6 67.6 7.17 27.6 58.6 72.0 23.33 61.1 78.0
85.2 ______________________________________
Table IV, above, shows the release of doxazosin as percent released
over time from the devices of Examples 8, 9 and 10. The rate of
release of doxazosin increased as the amount of PEG-600 in the
coating increased. Examination of the devices of Examples 8, 9 and
10 by scanning electron microscopy after release of doxazosin
resulted in the inability to locate any pores in the coating at a
0.1 micron lower limit of detection. Therefore, the doxazosin which
had a particle size greater than 0.1 micron exited from these
devices in solution. Nonetheless, the devices were capable of
releasing doxazosin in a controlled manner over time and, further,
the rate of release can be controlled by the amount of PEG 600 in
the coating. Of course, the limitation for such devices of Examples
8, 9 and 10 is that the beneficial agent(s) must be either soluble
in water or, perhaps, of a very small (less than 0.1 micron)
particle size.
TABLE V ______________________________________ Percent of Glipizide
Released over Time from Devices of Examples 11 and 12 Percent
Glipizide Released Device of Device of Time (hrs.) Example 11
Example 12 ______________________________________ 0 0 0 1.0 12.7
0.7 2.0 26.1 5.8 3.33 40.0 14.9 5.0 50.3 25.6 6.0 56.6 32.9 8.25
63.8 41.1 9.67 67.4 45.2 21.5 76.6 58.8
______________________________________
Table V, above, shows the release of glipizide, an insoluble drug,
as percent released over time from the devices of Examples 11 and
12. Examination of the devices of Examples 11 and 12 by scanning
electron microscopy following release of glipizide revealed the
presence in the coating of pores larger than 245 microns which had
been formed upon dissolution of the particulate sucrose.
EXAMPLE 14
Tablets (500 mg) were prepared from a powder blend consisting of
PEO-100K, sodium chloride, and glipizide in the weight ratio
76:20:4, using a Carver press under 2 metric tons for 2 seconds.
These tablets were spray-coated with a suspension of sucrose (60/80
mesh) in an acetone solution of cellulose acetate (2.5 wt %) and
PEG-600 (2.5 wt %). The final weight ratio of cellulose acetate to
PEG-600 to sucrose was 1:1:2. The final coating level was 16 weight
percent of the final coated tablet weight. The in vitro release of
glipizide from these tablets into 0.004M Tris, pH 8.7, was carried
out as described in Example 13 and glipizide was assayed by HPLC
using a 3.9 mm.times.15 cm Novapack C.sub.18 column (Waters
Associates, Milford, Mass.) with a mobile phase consisting of 50
volume percent 0.05M sodium phosphate (pH 7.5) and 50 volume
percent methanol. The flow rate was 1.0 ml/min. and detection of
glipizide was at 227 nm. The in vitro release kinetic profile,
shown in Table VI, below, demonstrates controlled release of
glipizide from these tablets.
TABLE VI ______________________________________ Percent of
Glipizide Released over Time from the Device of Example 14 Time
(hrs.) Percent Glipizide Released
______________________________________ 0 0 0.5 15.4 1.0 30.4 1.5
44.8 2.0 55.5 3.0 69.9 4.0 77.3 5.0 81.9 6.0 84.6 7.0 86.6 8.0 87.0
9.0 88.7 10.0 89.3 11.0 89.7 13.0 91.0 15.0 91.6
______________________________________
EXAMPLE 15
Bilayer tablets of the current invention are prepared as follows.
Polyethylene oxide (250 mg) of average molecular weight 300K
(PEO-300K) is lightly compressed in a Carver press using a 13/32
inch standard concave lower punch and a 13/32 inch flat upper
punch. Doxazosin mesylate is blended with PEO-100K in a ratio of
2:8, and 250 mg of this blend is poured onto the lightly compressed
PEO-300K layer in the Carver press. Using a 13/32 inch standard
concave upper punch, the two layers are compressed under 2 metric
tons for about 2 seconds. The tablets are spray-coated with a
suspension of sucrose (30/40 mesh) in an acetone solution of
cellulose acetate (4%) and PEG-600 (1%). The final weight ratio of
cellulose acetate to PEG-600 to sucrose is 4:1:5. The final coating
comprises 5-25 weight percent of the total coated tablet.
EXAMPLE 16
Spherical beads of the type shown in FIG. 4 are prepared as
follows. Doxazosin mesylate and PEO-100K are blended in the ratio
1:9. This blend is mixed with a small amount of water in a Hobart
mixer. The wet powder is transferred to a Fuji extruder (Fuji
Paudal Co., Tokyo, Japan), and short (1 inch.times.1/16 inch)
strands are formed. The extruded material is transferred to a Fuji
spheronizer (Fuji Paudal Co., Tokyo, Japan) which transforms the
material into beads of approximate diameter 0.5-1.5 mm. After
drying, the beads are spray-coated in a Freund CF-granulator
(CF-360; Freund Industrial Co., Tokyo, Japan) with an acetone
solution of cellulose acetate and HPC (1:1). Alternatively, the
drug/PEO beads are spray-coated with a suspension of sucrose
(preferably 100/200 mesh) in an acetone solution of cellulose
acetate and PEG-600. The final weight ratio of cellulose acetate to
PEG-600 to sucrose is 4:1:5; the final coating comprises 5-25
weight percent of the coated bead. An amount of coated beads
corresponding to the desired drug dose is filled into a gelatin
capsule.
EXAMPLE 17
Spherical multilayered beads of the type shown in FIG. 5 are
prepared as follows. PEO-300K is mixed with a small amount of water
in a Hobart mixer. The wet powder is transferred to a Fuji
extruder, and short (1 inch.times.1/16 inch) strands are formed.
The extruded material is transferred to a Fuji spheronizer which
transforms the material into beads of approximate diameter 0.5 mm,
which are subsequently dried. Doxazosin mesylate and PEO-100K are
blended in the ratio 2:8 and are dissolved in 1:1 methylene
chloride/methanol. The PEO-300K beads are coated with the doxazosin
mesylate/PEO-100K solution in a Freund CF-granulator. These beads
are extensively dried to remove solvents, and then are coated in a
Freund CF-granulator with an acetone solution of cellulose acetate
and HPC (1:1). Alternatively, the drug/PEO beads are spray-coated
with a suspension of sucrose (preferably 100/200 mesh) in an
acetone solution of cellulose acetate and PEG-600. The final weight
ratio of cellulose acetate to PEG-600 to sucrose is 4:1:5; the
final coating comprises 5-25 weight percent of the coated bead. An
amount of coated beads corresponding to the desired drug dose is
filled into a gelatin capsule.
EXAMPLE 18
Tablets providing a once daily sustained release dose of a
decongestant and an antihistamine are prepared as follows.
Polyethylene oxide of average molecular weight 100,000 (PEO-100K)
is blended with phenylpropanolamine hydrochloride and
chlorpheniramine maleate in the ratio 413:75:12. This blend is
compressed to form 500 mg tablets using a tablet press. Compressed
tablets are spray-coated with a suspension of sucrose (30/40 mesh)
in an acetone solution of cellulose acetate (4%) and PEG-600 (1%).
The final weight ratio of cellulose acetate to PEG-600 to sucrose
is 4:1:5. The final coating level is 7-25 weight percent of the
final coated tablet weight. The release kinetics of the two drugs
are assessed using methodology well known in the art, as
exemplified in Example 13. These kinetics are used to optimize the
rate and duration of drug release by further formulation changes,
for example, changes in the PEO molecular weight, the coating
level, the coating composition, and by the addition of tablet
excipients and/or osmotically effective solutes as will be obvious
to those experienced in the art based on the disclosure herein.
EXAMPLE 19
Tablets providing a sustained release dose of an
.alpha.-blocker/antihypertensive agent and a
diuretic/antihypertensive agent are prepared as follows:
polyethylene oxide of average molecular weight 100,000 (PEO-100K)
is blended with prazosin hydrochloride and polythiazide in the
ratio 476:20:4. This blend is compressed to form 500 mg tablets
using a tablet press. Compressed tablets are spray-coated with a
suspension of sucrose (30/40 mesh) in an acetone solution of
cellulose acetate (4%) and PEG-600 (1%). The final coating level is
7-25 weight percent of the final coated tablet weight. The release
kinetics of the two drugs are assessed using methodology well known
in the art, as exemplified in Example 13. These kinetics are used
to optimize the rate and duration of drug release by further
formulation changes, for example, changes in the PEO molecular
weight, the coating level, the coating composition, and by the
addition of tablet excipients and/or osmotically effective solutes,
as will be obvious to those experienced in the art based on the
current disclosure.
EXAMPLE 20
Bilayer tablets providing a once daily sustained release dose of a
decongestant and an antihistamine are prepared as follows. PEO-100K
is blended with phenylpropanolamine hydrochloride and
chlorpheniramine maleate in the ratio 76:150:24. A bilayer tablet
is formed with one layer comprising 250 mg of the PEO-100K/drug
blend, and the other layer comprising 250 mg PEO-300K, using a
Carver press as described in Example 15. Compressed bilayer tablets
are spray-coated with a suspension of sucrose (30/40 mesh) in an
acetone solution of cellulose acetate (4%) and PEG-600 (1%). The
final weight ratio of cellulose acetate to PEG-600 to sucrose is
4:1:5. The final coating level is 7-25 weight percent of the final
coated tablet weight. The release kinetics of the two drugs are
assessed using methodology well known in the art, as exemplified in
Example 13. These kinetics are used to optimize the rate and
duration of drug release by further formulation changes, for
example, change in the PEO molecular weight, the coating level, the
coating composition, and by the addition of tablet excipients
and/or osmotically effective solutes as known in the art and
described herein.
* * * * *